The presently disclosed and claimed inventive concepts relate to targeted therapeutic delivery systems and methods to treat cardiac disorders, in particular cardiac arrhythmias, and more particularly, but not by way of limitation, atrial fibrillations such as drug-refractory atrial fibrillation.
Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring treatment and frequently progresses from paroxysmal AF to permanent AF and accounts for nearly 20% of the strokes in the U.S. AF inflicted approximately 2.3 million Americans in 20041,2 and cost the health care system nearly $12 billion a year to treat AF and AF-related strokes.2 By the year 2050, the number of AF patients is projected to increase to 16 million as the population ages.3 Nearly half of AF patients are refactory (i.e., do not respond) to anti-arrhythmic drugs and require non-pharmacologic treatment, i.e., surgical or catheter ablation. Clinical trials aimed at a pharmacological treatment of AF resulted in a 50% success rate after one year follow-up. The other 50% have been shown to have drug and cardioversion resistance. These patients are now treated with costly and time consuming catheter based application of radiofrequency (RF) energy within the heart to isolate the focal firing sites in the pulmonary vein (PV) myocardial sleeves from the rest of the atria. Currently, there is only one RF ablation catheter approved by FDA for atrial ablation procedures. Off-label use of all other surgical ablation devices had raised significant regulatory concerns and Iitigations.4 Standard catheter or surgical ablation procedures produce lesion sets to isolate the pulmonary vein (PV)-atrial junction, containing the presumed triggers and/or substrate for AF.5-8 However, in a single procedure, PV antrum isolation only leads to approximately 60+-70+% success for the earliest stage of AF (paroxysmal AF) and less than 50% for more persistent forms of AF.5-8 This approach, widely practiced worldwide, has many drawbacks including relatively low success rate (˜70%) and various complications, including PV stenosis, cardiac tamponade, esophageal injury and minor or major strokes. Despite all the advances in ablation technologies in the past 6 years, success of AF ablation has not improved. The unsatisfactory efficacy of AF ablation is mainly due to insufficient understanding of the electrophysiological mechanism(s) underlying the initiation of AF and its progression into more persistent forms of AF. A mechanistically-based therapy is still lacking.
Prior studies of AF initiation in patients and animals indicate that (unbalanced) activation of both sympathetic and parasympathetic nervous systems often precede AF onset.9-14 Mammalian hearts are dually innervated by the extrinsic and intrinsic cardiac autonomic nervous system (CANS). It is known that the intrinsic CANS is a neural network composed of many ganglionated plexi and interconnecting nerves and/or neurons. 15-19 In this neural network, bilateral autonomic inputs come together at many “integration centers” before giving rise to final common pathways that control cardiac rhythm and force of contraction.15,16,18,19 These intrinsic integration centers are located in the ganglionated plexi (GP) which are overlain by epicardial fat pads. In mammalian hearts, four major atrial GP (anterior right GP, ARGP; inferior right GP, IRGP; superior left GP, SLGP; and inferior left GP, ILGP) are located adjacent to the junction of the atrium and four pulmonary veins.14-17 In previous studies, we have shown that electrical stimulation or injection of acetylcholine into the GP near the PV-atrial junction can initiate sustained AF arising from the PV-atrial junction.13,14,19 Ablation of the four major atrial GP and ligament of Marshall markedly suppress the inducibility and maintenance of AF in multiple animal models, including the rapid atrial pacing model.20,21 Notably, the lesion sets of a standard AF ablation (PV antrum isolation) involve ablation of two or three of the four major atrial GP, the ligament of Marshall and numerous autonomic nerves, indicating that autonomic denervation is a major contributor to the antiarrhythmic effects of AF ablation. Importantly, ablations involving only the major atrial GP, without PV antrum isolation, yielded similar results to the standard PV antrum isolation but produced significantly less collateral damage to the atrial myocardium and possible less iatrogenic left atrial flutter.22-24 While re-innervation may occur 1-6 month after RF catheter ablation procedures25-27, the clinical benefits of GP ablation lasted 16-18 months, 22-24 suggesting that permanent injury to the intrinsic CANS, particularly the autonomic neurons, may not be necessary to inhibit AF.
Targeted drug delivery is an increasingly used nanomedicine technology in which delivery of therapeutics to target tissues may increase drug efficacy, eliminate side effect and reduce costs. Polymeric nanoparticles whose diameters range from 10-300 nanometers28-36 can be formulated as nanocomposites with encapsulated drugs for burst and/or controlled release.31-33 Superparamagnetic nanoparticles, approved in the early 1990s for clinical magnetic resonance imaging enhancement, can be encapsulated in polymers or silicon and pulled into tissues to produce more precise lesion sets and thereby reducing collateral damages.
Standard AF ablation requires the creation of two circumferential lesions to isolate the antrum of all the PVs. Currently, atrial ablation strategies focus on isolating and/or destroying atrial tissue that presumably is responsible for AF, although the long-term consequences of extensive damage to the atrial myocardium, neural elements and atrial contractility are yet to be discovered.
Multiple basic science studies have demonstrated significant impact on AF after the major left atrial GPs were ablated. Using a rapid atrial pacing model, Lu et al showed that shortening of the effective refractory period (ERP), increase of ERP dispersion as well as increased AF inducibility caused by rapid atrial pacing for 3 hours were all reversed by ablation of the 4 major atrial GP and ligament of Marshall (LOM).48 In animals receiving GP ablation first, rapid atrial pacing for 6 hours failed to change the ERP, ERP dispersion and AF inducibility. The authors proposed that autonomic denervation may serve as a therapeutic modality to prevent paroxysmal AF to progress to more persistent forms of AF. Other animal studies also demonstrated that after ablation of the GP and LOM, AF became more difficult to initiate and sustain; normalization of the fractionated potentials often led to the termination of AF after GP ablation.62,63 Moreover, GP ablation may also convert AF from the focal form of AF to the macro-reentrant form of AF, which was more responsive to antiarrhythmic drugs.63 
Several clinical studies have indicated the benefits of autonomic denervation by targeting the major atrial GPs identified by high frequency stimulation. When GP ablation was combined with PV isolation, the success rate improved.37-39 Addition of PV isolation produced a long-term success rate higher than 90% in patients with paroxysmal AF.37,39 A series of recent manuscripts by Pokushalov et al also reported similar success rate in AF ablation targeting only the major atrial GPs in comparison to the standard PV isolation approach.40-42 
As noted, clinical studies demonstrated that GP ablation as an adjunct therapy to PV isolation improved the outcome of AF ablation whereas GP ablation alone produced a success rate similar to the standard PV isolation37-42. This denervation-only ablation strategy has the advantage of producing more focused lesion sets and potentially carrying a smaller risk of producing iatrogenic macro-reentrant left atrial tachycardia.
A method of direct (targeted) treatment of cardiac tissues for the inhibition of AF and other cardiac disorders with less extensive injury to cardiac tissues and which is non-permanent would be highly desirable.